β-Amyloid protein (hereinafter referred to as Aβ) is a major structural component of the senile plaques strikingly present in the brains of patients with Alzheimer's disease, and it is an insoluble peptide comprising 39 to 43 amino acids. It is produced by enzymic cleavage from β-amyloid protein precursor protein.
From recent detailed pathological research into the brains of patients with Alzheimer's disease it is reported that, in the process of the occurrence of dementia, first of all there is a build-up of Aβ within the brain of the patient, which triggers the formation of senile plaques, and after the passage of a considerable number of years there occurs neurofibrillary degeneration followed by neuronal degenerative loss [Ann. Rev. Neurosci., Vol. 12, 463 (1989)]
Furthermore, it is reported that Aβ which comprises 40 amino acids (Aβ1-40) and its active central portion peptide (Aβ 25-35) cause degeneration and death of rat primary hippocampal neurons in an in vitro experimental system and specifically lower the cellular MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] reduction capacity [see, respectively, Science, Vol. 250, 279 (1990) and J. Neurochem., Vol. 65, 2585 (1995)].
As examples of the cells exhibiting a lowering of the MTT reduction capacity due to Aβ, there are foetal rat hippocampal neurons, PC12 cells and HeLa cells, etc. Consequently, by measuring activity in inhibiting this lowering of the MTT reduction capacity due to Aβ in such cells, it is possible to investigate substances which inhibit the damaging action of Aβ on nerve cells.
Now, long-term potentiation (hereinafter referred to as LTP) is a phenomenon in which, by hippocampal nerve fibre electrical stimulation at high frequency for a short time, the synapse reaction strength is increased over a prolonged period, and it is regarded as a model for learning and memory. It is reported that, in hippocampal sections, Aβ has an LTP impairing action [J. Neurosci. Res. Vol. 60, 65 (2000), Proc. Natl. Acad. Sci. USA, Vol. 95, 6448 (1998), etc]. Furthermore, it is reported that, in a transgenic mouse overexpressing Aβ, LTP in the hippocampus is inhibited compared to normal mouse and, in a learning behaviour test, the memory and learning capacity are lowered [Science, Vol. 274 99 (1996)].
Consequently, by investigating substances which inhibit LTP impairment due to Aβ in the hippocampus, it is possible to investigate substances which lessen memory impairment caused by Aβ.
Aβ is regarded as at least one of the causes of the occurrence of Alzheimer's disease, so a substance which inhibits the impairment of nerve cells induced by Aβ would be effective as a preventive or remedy for Alzheimer's disease.
Examples of known compounds which suppress nerve cell toxicity due to Aβ are rifampicin [Biochem. Biophys. Res. Commun., Vol. 204, 76 (1994)], Congo Red [Proc. Natl. Acad. Sci. USA, Vol. 91, 12243 (1994) and AZ36041 [Biol. Pharm. Bull., Vol. 18, 1750 (1995), etc.
Moreover, (−)-huperzine A is an example of a compound reported to suppress LTP impairment in the hippocampus due to Aβ [Neurosci. Lett. Vol. 275 (3): 187-190 (1999)].
Illnesses which are characterized by the extracellular deposition in various organs and tissues of polymerized amyloid protein which adopts a specific fibrillar structure are generally classified as amyloidosis. The protein from which this amyloid is composed is, for example, in Alzheimer's disease, Aβ which is deposited in the brain; in type 2 diabetes, it is amylin which is deposited in the pancreas; in familial amyloid neuropathy, it is serum prealbumin (transthyretin) which is deposited in the peripheral nerves; it is immunoglobulin light chain-derived AL protein in the case of amyloidosis accompanying primary and multiple myeloma; and it is AA protein in the case of secondary amyloidosis, etc. [See, for example, Sipe, J. D., Annu. Rev. Biochem., Vol. 61, 947-97 (1992), etc.]
The fact that the amyloid protein in the course of fibril-formation produces a β-sheet structure is known to be a characteristic common to many amyloid proteins. [See, for example, Sipe, J. D., Annu. Rev. Biochem., Vol. 61, 947-97 (1992), etc.]
Aβ is a typical amyloid protein, and it accumulates in the brains of Alzheimer's disease patients, forming senile plaques. Within the senile plaques, a β-sheet structure is adopted and fibril formation occurs, and there is known to be characteristic staining by dyes such as thioflavin and Congo red which denote a fibrillar structure. Furthermore, it is known that with the adoption of the β-sheet structure and fibril formation, Aβ shows toxicity to cultured nerve cells [Pike, C. J. et al, J. Neurosci. Vol. 13, 1676-1687 (1993)]
It is also known that the amylin, which is the main structural component of the amyloid protein deposited in the pancreas in type 2 diabetes, adopts a β-sheet structure and forms fibrils, which show toxicity to pancreatic β-cells [Lorenzo, A. et al, Nature, Vol. 368, 756-760 (1994)].
It is reported that amyloid proteins such as Aβ and amylin both exhibit cytotoxicity by adopting a β-sheet structure and forming fibrils, and by lowering the cell MTT reduction capacity. Consequently, it is thought that compounds which inhibit this fibril formation by amyloid proteins like Aβ and amylin would inhibit their cell toxicity. Furthermore, since the mechanism of such manifestation of cytotoxicity is common to a number of amyloid proteins, it is believed that drugs which inhibit the cytotoxicity of certain amyloid proteins and suppress fibril-formation could also inhibit cytotoxicity and fibril-formation in other amyloid proteins.
Thus, as well as Alzheimer's disease and type 2 diabetes, by suppressing fibril-formation of amyloid protein this will be effective as a preventive or remedy for, for example, immunoglobulinic amyloidosis, reactive amyloidosis, familial amyloidosis, dialysis-related amyloidosis, senile amyloidosis, cerebrovascular amyloidosis, hereditary cerebral hemorrhage with amyloidosis, Creutzfeldt-Jakob disease, bovine spongiform encephalitis (BSE), scrapie, medullary carcinoma of the thyroid, insulinoma, localized atrial amyloid, amyloidosis cutis, localized nodular amyloidosis and other types of amyloidosis, preferably for Alzheimer's disease, type 2 diabetes, dialysis-related amyloidosis, familial amyloidosis, Creutzfeldt-Jakob disease and BSE, and in particular for Alzheimer's disease or type 2 diabetes.
Known examples of compounds which inhibit amyloid protein fibril-formation include variant peptide (WO96/28471), imino-aza-anthracyclinone derivatives derived from anthrazalone (WO98/32754), thionaphthalene derivatives with a specific structure (JP-A-9-95444) and isochroman compounds (JP-A-2000-198781). As compounds which inhibit fibril-formation by Aβ in particular from amongst the amyloid proteins, there are known iAβ5 [Nat. Med., Vol. 4, 822-826 (1998)], and PTI-00703 [Neurobiol. Aging, Vol. 19 (Suppl 4) 1070 (1998). However, these compounds have a structure which is completely different from the nitrogen-containing heteroaryl compounds which are the effective component of the amyloid protein fibril-formation inhibitors of the present invention.
With regard to nitrogen-containing heteroaryls, 3-[[4-[(2-fluoro-5-methylphenyl)amino]-2-pyrimidinyl]amino]-phenol and 4-[[6-[(2,5-dichlorophenyl)amino]-4-pyrimidinyl]amino]-phenol are disclosed as having an anticancer action (WO00/12485, WO00/12486, etc), and the analogous 4,6-dianilino-pyrimidine derivatives are also disclosed as having an anticancer action (Japanese Patent Publication (PTC) No. 9-506363). Moreover, 4,4′-[(6-methyl-2,4-pyrimidinediyl)diimino]bisphenol, 4,4′-[(6-amino-1,3,5-triazine-2,4-diyl)diimino]bisphenol and 4,4′-[2,4-pyrimidinediyldiimino]bisphenol are disclosed as having an antibacterial action or anti-HIV action [J. Indian Chem. Soc. Vol. 58 [5], 512-13 (1981), Acta Cienc. Indica. Chem. Vol. 11[1], 66-70 (1985), J. Med. Chem. Vol. 9(3), 423-4, (1966), WO99/36410, WO99/50250].
Moreover, it has been disclosed that triazine derivatives with a 4-position derivative have an impeding action for kinase which is an enzyme catalysing the reaction to produce ATP by transfer of a phosphoryl group within the cell, and are valuable in the treatment of Alzheimer's disease, etc (WO01/25220).